Manidipine 2HCl br Ghrelin interactions with the opioid syst

Ghrelin interactions with the opioid system The endogenous opioid system is an important regulator of appetite and metabolism (Bodnar, 2017, Nogueiras et al., 2012). In fact, several pharmacological studies have demonstrated that agonists of the three opioid receptors (mu, kappa, and delta) increase food intake, whereas antagonists of these receptors decrease food intake (Bodnar, 2016, Bodnar, 2018). Apart from these orexigenic effects, the opioid system regulates food reward and motivation. Opioids act on the mesolimbic DA system inducing DA release through activation of μ-opioid receptors in the VTA (Spanagel et al., 1992) and μ- and/or δ-opioid receptors in the NAc (Hirose et al., 2005, Yoshida et al., 1999), whereas κ-opioid receptors in the NAc decrease DA release (Spanagel et al., 1992). Both ghrelin and opioids act in the same areas, including the hypothalamus and the VTA, to regulate homeostatic feeding and food reward behaviors respectively (Ikeda et al., 2015, Romero-Pico et al., 2013, Skibicka et al., 2012b). In support of their functional interaction, ghrelin-induced chow intake and motivated behavior toward sucrose are blunted by the opioid receptor antagonist naltrexone (Skibicka et al., 2012b). Conversely, sub-chronic administration of ghrelin receptor antagonist was reported to increase the levels of Leu-enkephalin-Arg(6) in the NAc, of Met-enkephalin-Arg(6)Phe(7) in the VTA, and of dynorphin B in the hippocampus, providing evidence of cross-talk between ghrelin and the opioid system (Engel et al., 2015). Finally, ghrelin seems to be involved in the effects of opiates since pharmacological inhibition of ghrelin signaling diminishes morphine-induced locomotor activity, DA release in the NAc and increase in stereotypic behaviors in rodents (Sustkova-Fiserova et al., 2014). These results provide evidence for a high degree of interaction between ghrelin and the opioid system.
Ghrelin and endocannabinoids Several interactions between ghrelin and the endocannabinoid system have been reported at the periphery and in Manidipine 2HCl areas regulating food intake and energy balance, indicating a crosstalk between these two systems (Kola et al., 2008, Senin et al., 2013). Endocannabinoids have a strong implication in the control of feeding as indicated by their ability to increase consumption of palatable liquids and foods in satiated animals and motivated behaviors [see (Kirkham, 2009) for a review]. The cannabinoid CB1 receptor (CB1R) is mostly expressed on axon terminals (Herkenham et al., 1991). Cannabinoid agonists stimulate VTA DA neurons activity leading to increased release of DA within the NAc shell (French, 1997, Solinas et al., 2006), whereas a CB1R antagonist blunts the mesolimbic DA release elicited by the presentation of novel palatable foods (Melis et al., 2007, Oleson et al., 2012). Recently, the functional interaction between ghrelin and endocannabinoids was supported by studies showing that the peripheral, intra-VTA or intra-NAc administration of a ghrelin antagonist blocks the rise in anandamide and decrease in 2-arachidonoylglycerol levels induced in the NAc by fentanyl treatment (Sustkova-Fiserova et al., 2017). Conversely, the ghrelin-dependent DA release in the NAc and the consequent activation of locomotor activity appear to depend on cannabinoid signaling in the VTA. This hypothesis is based on studies in mice in which the systemic administration of a CB1R antagonist blunted the increase in DA and in locomotor activity induced by i.c.v. injection of ghrelin (Kalafateli et al., 2018). These effects were replicated when both CB1R antagonist and ghrelin were administered into the VTA (Kalafateli et al., 2018). These results point to the VTA as an important locus of interaction between ghrelin and the endocannabinoids.
Crosstalk between food reward and homeostatic mechanisms
Concluding remarks The mesolimbic system, including the VTA and the NAc, is the main final pathway for most ghrelin's actions on food reward-associated behaviors. Control of DA plays a key role in ghrelin actions on the reward system, which also involve endogenous opioid peptides and endocannabinoids. This interdependence shows the complexity of feeding control, in which multiple neurotransmitters are coordinated to achieve a proper behavioral and physiological equilibrium. In physiological conditions, the respective contribution of direct actions of ghrelin in the VTA and indirect effects through various afferents, including from the hypothalamus, is still an open question. In light of recent data indicating the existence of different DA neurons subtypes (Poulin et al., 2018), it will be very interesting to identify on which of these neurons ghrelin exerts direct or indirect effects.